β-cat/TCF, formed by β-cat and a TCF family member, serves as the effector of the developmental canonical Wnt signaling cascade. β-cat/TCFs can also function as effectors of metabolic hormones or growth factors during adulthood.

We have demonstrated recently that liver-specific expression of dominant-negative TCF7L2 (TCF7L2DN) led to impaired glucose disposal in both male and female mice. Increased hepatic lipogenesis, however, was observed in male but not in female mice. Our further investigations on such LTCFDN transgenic mouse model revealed the role of estradiol (E2) in stimulating β-cat/TCF activity. E2 reconstitution in WT mice with ovariectomy (OVX) restored the resistance of female mice to HFD induced body weight gain, insulin intolerance and elevation of hepatic lipogenic gene expression. Such beneficial effects of E2 reconstitution, however, were absent in LTCFDN female mice.

To identify downstream metabolic effector/s of Wnt signaling in regulating hepatic lipogenesis, we assessed metabolic hormone expression in LTCFDN and WT littermates. Curiously, hepatic but not adipose tissue FGF-21 level was reduced in male LTCFDN mice. We then directly assessed the effect of E2 on hepatic FGF-21 expression. In WT mice on LFD diet, OVX leads to reduced hepatic FGF-21 mRNA and protein levels, associated with reduced circulating FGF-21 hormone level. These reduction was associated with reduced hepatic β-cat S675 phosphorylation, TCF7 and TCF7L2 expression. In WT mice on HFD, OVX also reduced hepatic FGF-21 mRNA and circulating FGF-21 hormone levels. Such reduction was also restored with E2 reconstitution. Our study hence identified that FGF-21 is likely among the downstream effectors of E2-Wnt signaling cascade in hepatic lipid homeostasis.


W. Shao: None. Y. Badakhshi: None. T. Jin: None.


Canadian Institutes of Health Research (PJT159735)

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